In postmenopausal women, the estrogen level in breast cancer is at least 10 times higher than that in plasma, and it is considered that the high estrogen level in breast cancer is caused by hydrolysis of estrone sulfate into estrone by steroid sulfatase (estrone sulfatase). Therefore, steroid sulfatase inhibitors are considered to be effective therapeutic agents for treating estrone-dependent breast cancer, and they are also considered to be effective for preventing or treating other estrone-dependent diseases such as endometrial cancer, ovarian cancer, endometriosis and adenomyosis uteri. In addition, steroid sulfatase participates in androgen biosynthesis, and its inhibitors can also be effective for preventing or treating androgen-dependent diseases such as prostate cancer.
Estrone-3-sulfamate (EMATE) was reported to be a typical steroid sulfatase inhibitor [International Journal of Cancer, Vol. 63, p. 106 (1995); U.S. Pat. No. 5,616,574]. After that, however, it has been clarified that EMATE has an estrogenic effect, and it has been shown that EMATE is not useful for treatment of estrone-dependent diseases [Cancer Research, Vol. 56, p. 4950 (1996)]. Compounds with no estrogenic effect are desired as steroid sulfatase inhibitors.
As other steroid sulfatase inhibitors of steroid type, the following are known: estrone-3-methylthiophosphonate, estrone-3-methylphosphonate, estrone-3-phenylphosphonothioate, estrone-3-phenylphosphonate [Cancer Research, Vol. 53, p. 298 (1993); Bioorganic & Medicinal Chemistry Letters, Vol. 3, p. 313 (1993); U.S. Pat. No. 5,604,215]; estrone-3-sulfamate derivatives [Journal of Medicinal Chemistry, Vol. 37, p. 219 (1994)]; 3-desoxyestrone-3-sulfonate derivatives [Steroids, Vol. 58, p. 106 (1993); The Journal of Steroid Biochemistry and Molecular Biology, Vol. 50, p. 261 (1994)]; 3-desoxyestrone-3-methylsulfonate derivatives [Steroids, Vol. 60, p. 299 (1995)]; estrone-3-amino derivatives [The Journal of Steroid Biochemistry and Molecular Biology, Vol. 59, p. 83 (1996); U.S. Pat. No. 5,571,933, U.S. Pat. No. 5,866,603]; vitamin D3 derivatives [The Journal of Steroid Biochemistry and Molecular Biology, Vol. 48, p. 563 (1994)]; dehydroepiandrosterone derivatives [The Journal of Steroid Biochemistry and Molecular Biology, Vol. 45, p. 383 (1993); Biochemistry, Vol. 36, p. 2586 (1997)]; A-ring modified derivatives of estrone-3-sulfamate [The Journal of Steroid Biochemistry and Molecular Biology, Vol. 64, p. 269 (1998); WO98/24802, WO98/32763]; 17-alkylestradiol derivatives [Bioorganic & Medicinal Chemistry Letters, Vol. 8, p. 1891 (1998); Journal of Medicinal Chemistry, Vol. 42, p. 2280 (1999)]; 3-substituted-D-homo-1,3,5,(10)-estratriene derivatives (WO98/11124, WO99/27935); D-ring modified derivatives of estrone (WO98/42729, WO99/27936); BCD-ring(s) modified derivatives of estrone [Canadian Journal of Physiology and Pharmacology, Vol. 76, p. 99 (1998)]; and 17β-(N-alkylcarbamoyl)-estra-1,3,5(10)-triene-3-sulfamates and 17β-(N-alkanoylamino)-estra-1,3,5(10)-triene-3-sulfamates [Steroids, Vol. 63, p. 425 (1998); WO99/03876]. Recently, in addition, it has been reported that various estrone derivatives modified at 17-position have inhibitory activity against steroid sulfatase (WO99/33858).
On the other hand, as steroid sulfatase inhibitors of non-steroid type, the following are known: tetrahydronaphthol derivatives [Journal of Medicinal Chemistry, Vol. 37, p. 219 (1994)]; 4-methylcoumarin-7-sulfamate [Cancer Research, Vol. 56, p. 4950 (1996); WO97/30041]; tyramine derivatives and phenol derivatives [Cancer Research, Vol. 57, p. 702 (1997); Biochemistry, Vol. 36, p. 2586 (1997); The Journal of Steroid Biochemistry and Molecular Biology, Vol. 68, p. 31 (1999); U.S. Pat. No. 5,567,831]; flavonoids [The Journal of Steroid Biochemistry and Molecular Biology, Vol. 63, p. 9 (1997); WO97/32872]; 4-hydroxytamoxifen derivatives [The Journal of Steroid Biochemistry and Molecular Biology, Vol. 45, p. 383 (1993); Bioorganic & Medicinal Chemistry Letters, Vol. 9, p. 141 (1999)]; isoflavon derivatives [The Journal of Steroid Biochemistry and Molecular Biology, Vol. 69, p. 227 (1999)]; chromane derivatives (WO99/52890); etc.
It is also known that steroid sulfamates and tyramine derivatives have the effect of memory enhancement (U.S. Pat. No. 5,556,847, U.S. Pat. No. 5,763,492).
17-Amido derivatives (Compound A1) disclosed in WO99/03876 are limited to alkylcarbamoyl derivatives wherein an alkyl moiety has at least 4 carbon atoms and to alkanoylamino derivatives wherein an alkanoyl moiety has at least 5 carbon atoms, and it is believed that the long-chain alkyl group contained therein is important for their inhibitory activity against steroid sulfatase. [wherein Y1 and Y2 represent a hydrogen atom or a lower alkyl group; Y3 represents a hydrogen atom, or forms a bond together with Y4; Y4 represents a hydrogen atom, or forms a bond together with Y3; Y5 represents CONHY6 (wherein Y6 represents a straight chain alkyl group having 4 to 14 carbon atoms), or NHCOY7 (wherein Y7 represents a straight chain alkyl group having 4 to 14 carbon atoms)].
Compound A2, as 20-ester derivatives, is disclosed in WO99/33858. {wherein Y8 and Y9 represent a hydrogen atom or a lower alkyl group, or Y8 and Y9 form a nitrogen-containing heterocyclic group together with N adjacent thereto; Y10 represents a hydrogen atom, or forms ═CY12Y13 [wherein Y12 and Y13 are the same or different and represent a hydrogen atom, a lower alkyl group, CO2Y14 (wherein Y14 represents a hydrogen atom, a substituted or unsubstituted lower alkyl group, etc.), etc.] together with Y11; and Y11 represents a lower alkenyl group, a lower alkanoyl group, etc., or forms ═CY12Y3 (wherein Y12 and Y13 have the same meanings as defined above, respectively) together with Y10}.
As antiestrogens, Compound A3 and Compound A4 are disclosed in WO99/33859, however, it has not been known that these compounds will show inhibitory activity against steroid sulfatase. {wherein Y15 represents a hydrogen atom or an alkyl group; Y16 represents a hydrocarbyl group having at least one oxygen atom (—O—), sulfur atom (—S—) or nitrogen atom [—NY18— (wherein Y18 represents a hydrogen atom or an alkyl group)]; and Y17 represents a hydrogen atom, or a hydrocarbyl group having at least one oxygen atom (—O—), sulfur atom (—S—) or nitrogen atom [—NY18— (wherein Y18 has the same meaning as defined above)]; or Y16 and Y17 may form a heterocyclic group together with the carbon atom adjacent thereto}. {wherein (1) when m indicates an integer of 0 to 6, Y19 has the same meaning as defined for Y16 above, and Y20 represents a hydrogen atom or an alkyl group; and (2) when m is O, Y19 and Y20 may form a substituted or unsubstituted, 5-membered or 6-membered ring together with the carbon atom adjacent thereto}.
On the other hand, as reported in WO99/33858, it is considered that compounds having not only inhibitory activity against steroid sulfatase but also an antiestrogenic activity (activity of inhibition of estrogen effect or estrogen biosynthesis) are useful for treating or preventing steroid hormone-dependent diseases, and it is also considered to be useful for treating or preventing such diseases that phenol derivatives (desulfamoylated compounds) produced through hydrolysis of a sulfamate in vivo have an antiestrogenic activity.